Quality Control Lecture - 1​st​ Shifting

Introduction to Quality Control 

➢ A  tool  that  gives  the  assurance  that  products  conform  to  the  standard  and  specification 
through a system of inspection, analysis, & action. 
 
The standard for Medicine for human use 
➢ Quality 
➢ Safe 
➢ Efficacy 
 
Chemical purity 
➢ Described as complete freedom from foreign matter. 
 
Standards for chemical for pharmaceutical use are determined by several factors​: 
➢ Essential criterion is Safety 
➢ Stability 
 
Source of Impurities in Pharmaceutical Chemica​l: 
➢ Raw materials 
➢ Manufacturing process 
○ Starting materials & intermediates 
○ Reagents, solvents, & catalysts 
○ Reaction vessels 
➢ Chemical & Physical instability 
○ Chem instability 
○ Physical changes 
○ Reaction w/ container materials 
○ Temperature effects 
➢ Manufacturing hazards 
○ Particulate contamination 
○ Non-particulate contamination 
○ Cross-contamination 
○ Microbial contamination 
■ Water - always be tested 
■ Air conditioner 
○ Process errors 
○ Packing errors 
○ Particulate contamination 
■ Charred carbon 
■ Human hair 
 
 
 
 
 
 
 
 
 
 
 Biopharmaceutics Lecture - 1st Shifting
 
Introduction to Biopharmaceutics & Pharmacokinetics 
 
Outline of discussion 
1. Biopharmaceutics 
2. Pharmacokinetics 
3. Pharmacodynamics 
4. Pharmacogenetics 
5. Toxicokinetics 
 
Biopharmaceutics 
➢ Interrelationship  of  the  physicochemical  properties  of  the drug, the dosage form (drug product) 
in  which  the  drug  is  given,  and  the  route  of  administration  on  the  rate  and  extent  of  systemic 
drug absorption. 
 
Bioavailability 
➢ A measure of systemic availability of a drug 
 
Factors:  If Drug is: 
➢ Nature of the drug molecule  ➢ Therapeutically effective 
➢ Route of delivery  ➢ Toxic 
➢ Formulation of dosage form  ➢ No apparent effect 
 
Biopharmaceutics involves factors that influence​: 
1. Design of the drug product 
2. Stability of the drug within the drug product 
3. Manufacture of the drug product 
4. Release of the drug from the drug product 
5. Rate of dissolution/release of the drug from the absorption site 
6. Delivery of the drug to the site action 
 
Factors influencing Drug Availability 
Physicochemical Properties:  Formulation factors that may affect release of 
➢ Aqueous solubility  drug from dosage form: 
➢ Particle size  ➢ Excipients 
➢ Polymorphic form  ➢ Tablet hardness and disintegration 
➢ Salt form  ➢ Tablet coating 
➢ pKa/pKb 
➢ Partition coefficient 
 
Pharmacokinetics​ = Pharmakon + Kinesis 
 
Pharmacokinetics​: ADME 
 
The goal of Application of Pharmacokinetics: 
Assure maintenance of therapeutic drug concentration in the body while preventing danger of toxicity. 
 
Linear Pharmacokinetics 
➢ Maximum plasma concentration of the drug equals size of drug dose administered. 
➢ Most drugs follow Linear Pharmacokinetics 
 
Non-Linear Pharmacokinetics 
➢ Dose-dependent or capacity limited or saturation pharmacokinetics 
➢ Maximum plasma concentration of drug is not equal to size of drug dose administred 
○ Ex: Alcohol, Ceftriaxone, Salicylic acid 
 
Experimental Approaches 
➢ Biologic sampling techniques 
➢ Analytical methods of measurement of drugs and metabolites 
➢ Procedures that facilitate data collection and manipulation 
 
Theoretical Approaches 
➢ Pharmacokinetic model that predict drug disposition after drug administration 
 
Statistical Approaches 
➢ Used  for  pharmacokinetic  parameter  estimation  and  data  interpretation  for  designing  and 
predicting optimal dosing regimens 
➢ Applied to pharmacokinetic models to determine data error and structural model deviation 
 
Classical Pharmacokinetic 
➢ A study of theoretical models focusing mostly on model development 
 
Clinical Pharmacokinetic 
➢ Application of pharmacokinetic methods to drug therapy 
➢ Multidisciplinary  approach  to  individually  optimized  dosing  strategies  based  on  patient’s 
disease state and patient-specific considerations 
➢ Applied to TDM to prevent any adverse toxicity 
○ Monitoring of plasma concentrations or pharmacodynamic endpoint/s 
 
Therapeutic Drug Monitoring 
➢ Monitor very potent drugs 
 
Population Pharmacokinetic 
➢ Study of pharmacokinetic differences of drugs in various population groups 
 
Pharmacodynamic 
➢ Relationship  between  the  drug  concentration  at the site of action (receptor) and pharmacologic 
response 
➢ Includes  biochemical  and  physiologic  effects  that  influence  the  interaction  of  drug  with  the 
receptor 
 
Receptor 
➢ Component  of  the  cell  or  organism  that  interacts  with  a  drug  and  initiates  a  chain  of  events 
leading to the drug’s observed effects 
Agonist 
➢ Drugs that occupy receptors and activate them 
 
Antagonist - can be Chemical or Physiologic 
➢ Drugs that occupy receptors but do not activate them 
➢ Blocks receptor activation by agonists 
➢ Competitive 
○ Competes w/ the activator to the receptor 
○ Reversible 
 
 ➢ Non-competitive 
○ Does not compete usually covalent bond. 
○ Irreversible 
 
Full activation: Agonist 
Less activation: Agonist & Antagonist 
No activation: Antagonist 
 
Drug Exposure - How much drug the patient has absorbed 
➢ Refers  to  dose  and  various  measures  of acute or integrated drug concentrations in plasma and 
biological fluid 
 
 
Drug Response - Pharmacologic effect of the drug 
➢ Refers to the direct measure of the pharmacologic effect of the drug 
➢ Includes endpoints or biomarkers from:  
○ remote,  presumed  mechanistic  effect  to  a  potential  or  accepted  surrogate  and  to  a  full 
range short/long term clinical effect 
 
Pharmacogenetics 
➢ Unusual drug responses that have a genetic or hereditary basis 
➢ Idiosyncratic - unusual response 
➢ Hyporeactivity - less response to the drug 
➢ Hyperreactivity - too much response to the drug 
 
Genetic polymorphism 
➢ Differences in response to a drug by different individual modulated by ​genetic predisposition 
➢ Example:  
○ Slow acetylator: prone to toxicity 
■ Isoniazid - neurotoxicity 
 
Toxicokinetics -animal studies 
➢ Application  of  pharmacokinetic  principles  to  the  design,  conduct  and  interpretation  of  drug 
safety evaluation studies and in validating dose-related exposure in animals 
➢ Performed in animals during preclinical drug development 
 
Clinical Toxicology - what can you do to avoid toxic metabolite 
➢ Study of adverse effects of drugs and toxic substances in the body 
➢ Pharmacokinetics  of a drug in an overmedicated (intoxicated) patient may be very different from 
the pharmacokinetics of the same drug given in lower therapeutic doses 
➢ Drugs involved in toxicity cases:  
○ acetaminophen, salicylates, morphine, and TCAs 
 
 
Invasive  Non-Invasive 
➢ Blood, spinal fluid, synovial fluid, tissue  ➢ Urine, saliva, feces, expired air or any 
biopsy, any biologic material that ​requires  biologic material ​without parenteral​ or 
parenteral or surgical intervention  surgical intervention 
 
Preclinical - animals, in vivo, in vitro 
Clinical - humans 
 
Drug Concentration in Blood, Plasma, or Serum 
➢ Most direct approach to assessing drug’s pharmacokinetic profile 
○ Whole blood – RBC, WBC, platelets, albumin 
○ Serum – blood is allowed to clot then centrifuged 
○ Plasma – addition of anticoagulant then centrifuged 
➢ Unbound drug concentration 
➢ Total plasma concentration 
 
Plasma Drug concentration-time Curve 
➢ Generated  by  obtaining  drug  concentration  in  plasma  samples  taken  at  various  time  intervals 
after administration of drug product 
➢ The  concentration  of  drug  in  each  plasma  sample  is  plotted  on  a  graph  paper  against  the 
corresponding time at which the plasma sample was obtained 
 
MEC - Minimum Effective Concentration 
➢ Reflects  the  minimum  concentration  of  drug  needed  at  the  receptors  to  produce  the  desired 
pharmacologic effect 
 
MTC - Minimum Toxic Concentration 
➢ Represents the drug concentration needed to just barely produce a toxic effect 
 
Therapeutic Window 
➢ The concentration between MTC and MEC 
 
Therapeutic Index 
➢ Ratio between toxic and therapeutic dose  
 
Wide therapeutic index is safer: 
➢ Less chance of overdosing or exhibiting MTC 
 
Onset Time 
➢ Time required for the drug to reach the MEC 
 
Duration of the Drug 
➢ Difference between the onset time and the time for the drug to decline back to the MEC 
 
The ​intensity of the pharmacologic effect​ is ​proportional​ to the ​number of drug receptors occupied​, 
which is reflected in the observation that ​higher plasma drug concentrations produce a greater 
pharmacologic response, up to a maximum. 
 
Time of Peak Plasma Level - Tmax 
➢ Time  of  maximum  drug  concentration  in  the  plasma  and  is  a  rough  marker  of  average  rate  of 
drug absorption 
 
Peak Plasma Level or Maximum Drug Concentration 
➢ Related to the dose, the rate constant for absorption, and the elimination constant of the drug 
 
Peak Concentration - Cmax 
➢ Maximum amount of drug concentration in your plasma 
 
AUC - Area Under the Curve 
➢ Related to the amount of drug absorbed systemically 
➢ A measure of bioavailability 
 
Drug concentrations in Tissue 
➢ Tissue biopsy  
➢ Verify malignancy 
➢ Ascertain if drug reached a particular site and verify concentration 
 
Drug concentrations in Urine and Feces 
➢ Indirect method to ascertain bioavailability of drug 
○ Urine - rate and extent of systematic absorption 
○ Feces - expelled by biliary secretion 
➢ For mass balance studies 
 
Drug concentrations in Saliva 
➢ Only the free drug diffuses into the saliva  
➢ Saliva/plasma drug concentration ratio is <1 for many drugs 
○ Influence by pKa of drug and pH of saliva 
➢ Serves as a secondary indicator only